Chronic heart failure is the leading cause for hospitalization in the US, affecting over five million patients, with over a half million newly diagnosed cases each year. Current therapies do not address the central pathophysiology underlying the development of heart failure, namely, the loss of functional cardiomyocytes. Therefore, cardiac progenitor cells hold enormous potential for therapeutic cardiac repair and regeneration. We and others have recently confirmed the existence of one such progenitor cell population in adult murine myocardium. These so-termed cardiac side population (CSP) cells are identified in adult hearts by their distinct Hoechst 33342 dye extrusion properties, and represent a distinct progenitor cell population. While in-vitro these CSP cells are capable of both biochemical and more importantly, functional cardiomyogenic differentiation, in- vivo such differentiation occurs at an exceedingly limited rate, and is limited by the mechanisms regulating cellular survival, proliferation and differentiation. CSP cells express a unique set of ATP binding cassette (ABC) transporters, including the breast cancer resistant protein (Abcg2/Bcrp1). While these ABC transporters confer the Hoechst dye efflux properties characteristic of SP cells, emerging evidence has also suggested that members of the ABC transporter family may serve as a conduit for the interaction of stem cells with their local environment, thereby mediating the intricate regulation of progenitor cell fate and function in response to external and internal stimuli. Indeed, our preliminary data demonstrate that Abcg2/Bcrp1 expression is gradually down- regulated during the first few weeks of post-natal development and is sharply up-regulated again in response to cardiac injury, in close correlation with CSP proliferation capacity. Furthermore, through gain and loss of function experiments, our data also demonstrate that the dynamic expression of Abcg2/Bcrp1 plays a critical role in the protection and functional regulation of CSP cells in both normal myocardium and following injury. Little is known about the control of dynamic Abcg2/Bcrp1 expression and its subsequent regulation of CSP proliferation and function. Thus, utilizing a multidisciplinary approach of in-vitro and in-vivo methodologies, here, we propose to determine (a) the molecular mechanism(s) controlling Abcg2/Bcrp1 expression and (b) the role of Abcg2/Bcrp1 in regulating the biological function of cardiac SP cells during post-natal development and following injury. Data obtained from this application will provide the first insight into the role of ABCG2/Bcrp1 in cardiac progenitor cells as well as provide novel molecular targets for enhancing therapeutic cardiac regeneration. PUBLIC HEALTH RELEVANCE Cardiovascular disease remains the single greatest cause of death in the Westernized world, claiming more lives in the US than the four next leading causes, combined. Among cardiovascular disease, the incidence of heart failure continues to rise at a staggering rate. Recent identification of the existence of cardiac stem/progenitor cells highlights the therapeutic potential of using these cells in cardiac repair and regeneration. However, our limited understanding of the biology of these cardiac progenitor cells and the regulation of their proliferation and differentiation prevents us from realizing the full potential of such intervention. The results obtained from our proposal will fill this gap and contribute to our understanding of molecular regulation of these cardiac progenitor cells.